5-羟色胺转运蛋白显像剂~*I-ADAM临床前药理研究

Preclinical pharmacological study on ~*I-ADAM as a serotonin transporter ligand

目的评价I2((2((二甲基胺基)甲基)苯基)硫)5碘苯胺(ADAM)的体内生物学特性。方法通过大鼠体内和脑内生物分布、Paroxetine阻断实验、大鼠血药清除动力学、大鼠脑放射自显影和异常毒性实验,对ADAM与5羟色胺转运蛋白(SERT)的结合特性进行评价。结果131IADAM大鼠脑摄取高,注射后2min组织百分注射剂量率(%IDorgan)达1087,在富含SERT的丘脑中的特异摄取随时间延长而增加,滞留时间长(60～240min),其特异摄取在注射后60,120和240min分别为294,303和309。用Paroxetine阻断后60min,丘脑的特异摄取比对照组明显下降(由294减至0148),而用Ketanserin阻断后,丘脑的特异摄取不受影响。放射自显影结果示,在注射Paroxetine后,丘脑小脑比值从794±039降至130±056,与对照组比较差异明显。甲状腺摄取在注射后2和120min分别为0009和1421%IDorgan。125IADAM大鼠血药清除动力学符合血药动力学二室模型,分布半衰期T12α=1379min,清除半衰期T12β=35714min,K12=0046min-1,K21=0018min-1,K10=0011min-1,表观分布体积Vd=022L,曲线下面积(AUC)=42175,拟合的曲线方程为C=36147·e-00725t+10413e-00028t。异常毒性实验结果示,小鼠的耐受剂量为人的1000倍。结论131IADAM初始进脑量高,与SERT结合具有高度特异性,清除快,毒性小。

Objective To evaluate the new ligand: *I-2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM) as a serotonin imaging agent. Methods Biological evaluations were performed in rats and mice. Results Biodistribution studies in rats showed that the initial uptake of ~131 I-ADAM in the brain was high (1.087%ID/organ at 2 min postinjection), and consistently displayed the highest binding (between 60～240 min postinjection) in hypothalamus, a region with the highest density of serotonin transporter (SERT). The specific binding [(T/CB)-1] of ~131 I-ADAM in hypothalamus was 2.94, 3.03 and 3.09 at 60, 120 and 240 min postinjection, respectively. The (T/CB)-1 was significantly blocked by pretreatment with Paroxetine, which is known as a serotonin site reuptake inhibitor, while another nonselective competing drug, Ketanserin, showed no blocking effect. The rat brain autoradiography and analysis showed that there was high ~131 I-ADAM uptake in hypothalamus, the ratio of hypothalamus/cerebellum was significantly reduced from 7.94±0.39 to 1.30±0.56 by pretreatment with Paroxetine at 60 min postinjection. Blood clearance kinetics was studied in rats, and the initial half-life of 13.79 min and late half-life of 357.14 min were obtained. The kinetic equation was: C=3.6147·e^-0.0725 t +1.0413 e^-0.0028 t . The thyroid uptake was 0.009 and 1.421%ID/organ at 2 min and 120 min postinjection, respectively, suggesting that in vivo deiodination maybe the major route of metabolism. Toxicity trial showed that the dose per kilogram administered to mice was 1000 times greater than that to human beings, assuming a body-weight of 50 kg. Conclusion These data suggest that ~131 I-ADAM may be useful for SPECT imaging of SERT binding sits in the brain.